TRAILBLAZER-ALZ 3 (NCT05026866) — Donanemab for Preclinical Alzheimer's Disease

Executive Summary

Executive Summary

This Phase 3 clinical trial, known as TRAILBLAZER-ALZ 3, evaluates donanemab (Kisunla®, LY3002813) in individuals with preclinical Alzheimer's disease - cognitively normal people who have biomarker evidence of amyloid pathology but have not yet developed clinical symptoms. This groundbreaking trial represents a paradigm shift toward preventive treatment of Alzheimer's disease, aiming to intervene before irreversible neurodegeneration occurs.

The trial is conducted by Eli Lilly and Company and represents the next step in the successful donanemab development program, building on the positive results from TRAILBLAZER-ALZ 2 (which led to FDA approval in 2024) by extending the intervention to an even earlier disease stage.

Trial Overview

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT05026866 |
| Trial Name | TRAILBLAZER-ALZ 3 |
| Phase | Phase 3 |
| Status | Active, not recruiting |
| Sponsor | Eli Lilly and Company |
| Enrollment | 2,996 participants |
| Enrollment Type | Estimated |
| Study Type | Interventional |
| Start Date | August 27, 2021 |
| Completion Date | November 1, 2027 |
| Last Updated | January 21, 2026 |

The Preclinical Alzheimer's Disease Concept

Defining Preclinical AD

Preclinical Alzheimer's disease represents the earliest detectable stage of AD pathology, occurring years to decades before the emergence of clinical symptoms. This concept has revolutionized our approach to AD research and treatment development.

According to the NIA-AA research framework, AD is conceptualized as a biological continuum:

| Stage | Characteristics | Clinical Status |
|-------|----------------|-----------------|
| Stage 1 | Amyloid positivity only | Cognitively normal |
| Stage 2 | Amyloid + subtle cognitive changes | Cognitively normal |
| Stage 3 | Amyloid + cognitive decline | MCI due to AD |
| Stage 4 | Mild dementia | Dementia due to AD |

TRAILBLAZER-ALZ 3 targets individuals in Stage 1-2 - those with amyloid pathology but no measurable cognitive impairment.

Why Target Preclinical AD?

The rationale for preclinical intervention is compelling:

• Amyloid plaques begin accumulating 20-30 years before clinical diagnosis
• Neuronal loss is already underway by the time MCI appears
• Early intervention may prevent irreversible damage

• The brain's compensatory mechanisms are still intact
• Synaptic and neuronal populations are preserved
• Treatment may have greater efficacy

• Disease-modifying treatments at later stages can only slow progression
• Preclinical intervention may prevent the development of symptoms entirely
• May preserve function and quality of life

• Lower plaque burden means faster and more complete clearance
• Less time required for amyloid removal
• Potentially shorter treatment duration needed

Biomarker Evidence for Preclinical AD

The ability to identify preclinical AD relies on biomarkers:

| Biomarker | What It Measures | Preclinical Significance |
|-----------|------------------|-------------------------|
| Amyloid PET | Amyloid plaque burden | Elevated in Stage 1 |
| CSF Aβ42/40 | Amyloid processing | Decreased in Stage 1 |
| Plasma p-tau181/217 | Tau pathology | Elevated in Stage 2 |
| FDG-PET | Brain metabolism | Normal in Stage 1, subtle changes in Stage 2 |
| MRI | Brain structure | Normal in Stage 1 |

Donanemab: Mechanism and Background

What is Donanemab?

Donanemab is a monoclonal antibody that targets pyroglutamate-modified amyloid-beta (pE3-Aβ) - a particularly toxic form of amyloid that is present in plaques. It was developed by Eli Lilly and received FDA approval in July 2024 for treatment of early-stage AD.

Antibody Properties

• Target: Pyroglutamate-modified amyloid-beta (pE3-Aβ) plaques
• Epitope: N-terminal truncation with pyroglutamate modification
• Mechanism: Antibody binds plaques, triggers microglial clearance via Fc-mediated phagocytosis
• Administration: Intravenous infusion every 4 weeks

Differentiation from Other Anti-Amyloid Antibodies

| Antibody | Target | Epitope | FDA Status |
|----------|--------|---------|------------|
| Donanemab | Plaques (pE3-Aβ) | N-terminal pyroglutamate | Approved 2024 |
| Lecanemab | Protofibrils | Aβ1-16 | Approved 2023 |
| Aducanumab | Plaques | Aβ3-7 | Withdrawn |

The pyroglutamate modification makes this epitope particularly relevant because:

• pE3-Aβ is highly fibrillar and stable
• It represents an early form of plaque
• Antibodies targeting this epitope may be more effective at plaque removal

Clinical Development History

TRAILBLAZER-ALZ (Phase 2)

• Results: Met primary endpoint (iADRS), 32% slower decline
• Population: Early symptomatic AD (MCI and mild dementia)
• Key finding: Significant amyloid plaque reduction

TRAILBLAZER-ALZ 2 (Phase 3)

• Population: Early symptomatic AD (MCI and mild dementia)
• Results: 35% slowing of clinical decline on iADRS, 36% on CDR-SB
• Approval: FDA approval July 2024 for early AD treatment

TRAILBLAZER-ALZ 3 (Phase 3, current)

• Population: Preclinical AD (cognitively normal, amyloid-positive)
• Goal: Prevent development of clinical symptoms

Study Design

Trial Type

This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial - the gold standard for establishing efficacy and safety.

Design Features

The TRAILBLAZER-ALZ 3 design incorporates several key features:

Population Characteristics

The trial enrolls individuals who are:

• Cognitively normal: No measurable cognitive impairment on standard testing
• Biomarker-positive: Evidence of amyloid pathology (PET or CSF)
• At risk: Likely to develop symptoms within the study timeframe
• Age-appropriate: Typically 60-80 years old

Treatment Regimen

| Parameter | Details |
|-----------|---------|
| Drug | Donanemab (LY3002813) |
| Dose | Tiered dosing (700 mg then 1400 mg Q4W) |
| Duration | Approximately 2 years |
| Route | Intravenous infusion |
| Loading | 3 initial doses at higher level |

The tiered dosing approach:

• Loading phase: Higher initial doses for faster amyloid reduction
• Maintenance: Standard dose for sustained effect
• Optional stop: Treatment may be discontinued after amyloid clearance

Primary Endpoint

Time to Clinical Progression

The primary endpoint is time to clinical progression measured by the Clinical Dementia Rating Global Score (CDR-GS).

What is Clinical Progression?

For this trial, clinical progression is defined as:

• CDR-GS change from 0 to ≥0.5
• This represents transition from cognitively normal to Mild Cognitive Impairment (MCI)

Why This Endpoint?

Assessment Methods

• CDR: Semi-structured interview with participant and informant
• Domains: Memory, orientation, judgment, problem-solving, community affairs, home/hobbies, personal care
• Scoring: Each domain 0-3, global score derived from scores

Secondary Endpoints

The trial includes multiple secondary endpoints to fully characterize treatment effects:

Cognitive Endpoints

• ADAS-Cog13: Alzheimer's Disease Assessment Scale - Cognitive subscale
• MMSE: Mini-Mental State Examination
• Rey Auditory Verbal Learning Test: Verbal memory assessment

Functional Endpoints

• ADCS-ADL: Alzheimer's Disease Cooperative Study - Activities of Daily Living
• Functional Activities Questionnaire: Daily functioning assessment

Biomarker Endpoints

• Amyloid PET: Change in plaque burden (Centiloid)
• Tau PET: Change in regional tau accumulation
• CSF biomarkers: Aβ42/40, total tau, phosphorylated tau
• MRI: Brain volume changes

Safety Endpoints

• Adverse events: Incidence and severity
• ARIA: Amyloid-related imaging abnormalities
• Laboratory changes: Hematology, chemistry

Rationale and Significance

Why Donanemab for Preclinical AD?

The extension of donanemab to preclinical AD is based on:

Potential Impact

If successful, TRAILBLAZER-ALZ 3 could:

Challenges and Considerations

Comparison with Other Prevention Trials

Similar Prevention Initiatives

| Trial | Intervention | Population | Status |
|-------|--------------|------------|--------|
| A4 Study | Solanezumab | Preclinical AD | Completed (negative) |
| DIAN-TU | Various | Autosomal dominant AD | Ongoing |
| GenerAtor | Various | At-risk populations | Ongoing |
| TRAILBLAZER-ALZ 3 | Donanemab | Preclinical AD | Ongoing |

Lessons from A4

The A4 (Anti-Amyloid in Asymptomatic Alzheimer's) trial tested solanezumab in preclinical AD but did not meet its primary endpoint. This taught important lessons:

TRAILBLAZER-ALZ 3 builds on these lessons with a more potent antibody and better-designed endpoint.

Patient Perspective

Who Might Qualify?

Individuals who:

• Are 60-80 years old
• Are cognitively normal (no memory complaints, normal test scores)
• Have evidence of amyloid in the brain
• Have a study partner (family member or friend)
• Are willing to undergo extensive testing

What Participation Involves

• Screening: Cognitive testing, PET scans, MRI, lumbar puncture
• Treatment: Monthly infusions for up to 2 years
• Monitoring: Regular cognitive testing, brain scans, safety assessments
• Follow-up: Extended follow-up after treatment discontinuation

Potential Benefits

• Access to investigational therapy
• Regular monitoring of brain health
• Contribution to Alzheimer's research
• Potential to slow or prevent cognitive decline

Potential Risks

• Infusion reactions
• Amyloid-related imaging abnormalities (ARIA)
• Unknown long-term effects
• Time commitment

Scientific Context

Amyloid Cascade and Prevention

The amyloid cascade hypothesis proposes that amyloid accumulation is the initiating event in AD, leading to:

If this hypothesis is correct, removing amyloid before symptoms emerge should prevent the downstream cascade entirely. TRAILBLAZER-ALZ 3 tests this hypothesis directly.

The "Window of Opportunity"

Research suggests there is a critical window for amyloid removal:

• Before symptoms: Greatest potential for prevention
• Early symptoms: Significant benefit possible
• Moderate disease: Modest benefit only
• Advanced disease: Minimal benefit

Current Status and Timeline

Trial Progress

• Start date: August 27, 2021
• Enrollment: Approximately 3,000 participants enrolled
• Status: Active, not recruiting
• Completion: November 2027

Expected Results

Results are expected in the 2026-2027 timeframe, which will:

• Determine if donanemab can prevent symptomatic AD
• Establish the role of anti-amyloid therapy in prevention
• Inform future prevention strategies

Related Pages

Alzheimer's Disease Topics

• [Alzheimer's Disease](/diseases/alzheimers-disease) — Comprehensive overview
• [Amyloid Beta](/proteins/amyloid-beta) — Target protein
• [Tau Protein](/proteins/tau) — Downstream pathology
• [Preclinical Alzheimer's Disease](/mechanisms/preclinical-alzheimers-disease) — Early stage

Related Clinical Trials

• [Donanemab TRAILBLAZER-ALZ 2 (NCT04468657)](https://clinicaltrials.gov/study/NCT04468657) — Early AD trial
• [Lecanemab (NCT01767311)](https://clinicaltrials.gov/study/NCT01767311) — Similar antibody
• [A4 Study (NCT02008357)](https://clinicaltrials.gov/study/NCT02008357) — Previous prevention trial

Therapeutic Approaches

• [Anti-Amyloid Immunotherapy](/mechanisms/anti-amyloid-immunotherapy) — Mechanism overview
• [Disease-Modifying Therapies](/therapeutics/disease-modifying-alzheimers) — Pipeline overview

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT05026866)
• [PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT05026866)
• [Eli Lilly Donanemab Information](https://www.lilly.com/donanemab)

References